Key pointsr Gestational diabetes mellitus is a common complication of pregnancy, but its effects on the offspring are poorly understood.r We developed a rat model of diet-induced gestational diabetes mellitus that recapitulates many of the clinical features of the disease, including excessive gestational weight gain, glucose intolerance, hyperinsulinaemia and mild hyperglycaemia.r Compared to the offspring of lean dams, exposure to gestational diabetes mellitus during the prenatal period resulted in obesity, hepatic steatosis and insulin resistance in young rat offspring that consumed a postnatal diet that was low in fat.r The combination of maternal gestational diabetes mellitus and the postnatal consumption of a high-fat diet by the offspring caused a more severe metabolic phenotype.r Metabolomic profiling of the liver tissues of the offspring of gestational diabetic dams revealed accumulation of lipotoxic lipids and reduced phosphatidylethanolamine levels compared to the offspring of lean dams.r The results establish that gestational diabetes mellitus is a driver of hepatic steatosis and insulin resistance in the offspring.Abstract Maternal obesity is associated with a high risk for gestational diabetes mellitus (GDM), which is a common complication of pregnancy. The influence of maternal obesity and GDM on the metabolic health of the offspring is poorly understood. We hypothesize that GDM associated with maternal obesity will cause obesity, insulin resistance and hepatic steatosis in the offspring. Female Sprague-Dawley rats were fed a high-fat (45%) and sucrose (HFS) diet to cause maternal obesity and GDM. Lean control pregnant rats received low-fat (LF; 10%) diets. To investigate the interaction between the prenatal environment and postnatal diets, rat offspring were assigned to LF or HFS diets for 12 weeks, and insulin sensitivity and hepatic steatosis were evaluated. Pregnant GDM dams exhibited excessive gestational weight gain, hyperinsulinaemia and hyperglycaemia. Offspring of GDM dams gained more weight than the offspring of lean dams due to excess adiposity. The offspring of GDM dams also developed hepatic steatosis and insulin resistance. The postnatal consumption of a LF diet did not protect offspring of GDM dams against these metabolic disorders. Analysis of the hepatic metabolome revealed increased diacylglycerol and reduced phosphatidylethanolamine in the offspring of GDM dams compared to offspring of lean dams. Consistent with altered lipid metabolism, the expression of CTP:phosphoethanolamine cytidylyltransferase, and peroxisomal proliferator activated receptor-α mRNA was reduced in the livers of GDM offspring. GDM exposure programs gene expression and hepatic metabolite levels and drives the development of hepatic steatosis and insulin resistance in young adult rat offspring.

Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic β-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired β-cell adaptation. Understanding these pathways, as well as mechanisms of β-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM.

The incidence of obesity and type 2 diabetes mellitus have risen across the world during the past few decades and has also reached an alarming level among children. In addition, women are currently more likely than ever to enter pregnancy obese. As a result, the incidence of gestational diabetes mellitus is also on the rise. While diet and lifestyle contribute to these trends, population health data show that maternal obesity and diabetes during pregnancy during critical stages of development are major factors that contribute to the development of chronic disease in adolescent and adult offspring. Fetal programming of metabolic function, through physiological and (or) epigenetic mechanisms, may also have an intergenerational effect, and as a result may perpetuate metabolic disorders in the next generation. In this review, we summarize the existing literature that characterizes how maternal obesity and gestational diabetes mellitus contribute to metabolic and cardiovascular disorders in the offspring. In particular, we focus on animal studies that investigate the molecular mechanisms that are programmed by the gestational environment and lead to disease phenotypes in the offspring. We also review interventional studies that prevent disease with a developmental origin in the offspring.

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Fetal exposure to gestational diabetes mellitus (GDM) is associated with a higher risk of youth-onset insulin resistance and type 2 diabetes. We have previously shown that the rat offspring of GDM dams are insulin resistant when compared to the offspring of lean dams. Since inflammation influences insulin sensitivity, we examined the impact of fetal exposure to GDM on inflammatory responses in the offspring. In rats, we compared inflammatory activity in newborn pups as well as 16week-old young-adult offspring from lean control dams with offspring from high fat and sucrose diet (HFS)-induced GDM dams. To determine whether there are additive effects of exposure to GDM and post-weaning diets, offspring of lean and GDM dams were fed either low fat or HFS diets until 16weeks of age. Plasma levels of interleukin(IL)-1β were elevated in the offspring of GDM dams. To determine whether this was related to immune reactivity, spleen cells from both the newborn and 16week-old offspring were isolated and reactivity to the toll-like receptor activators, pam3CSK4 and lipopolysaccharides were measured over a 72h timeframe. Spleen cells of GDM dams exhibited sustained stimulation of interleukin(IL)-1β and IL-10 production, whereas IL-1β and IL-10 synthesis diminished over time in spleen cells from the offspring of lean dams. Additive effects of GDM exposure and post-weaning HFS diet were not observed, suggesting the effects of GDM on cytokine production are independent of the post-weaning diet. Thus, we conclude that exposure to GDM in utero may condition the immune reactivity of spleen cells.

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IntroductionGestational diabetes mellitus (GDM) is a common pregnancy‐related health condition. While genetics, lifestyle and diet contribute to development of GDM, evidence suggests that low levels of adiponectin increases the risk for GDM. Adiponectin is a fat derived hormone that improves the sensitivity of tissues to insulin. We hypothesize that adiponectin deficiency causes fatty liver during pregnancy, ultimately contributing to the development of GDM.MethodsWe compared the glucose and insulin tolerance of pregnant (3rd trimester) adiponectin−/− (strain B6;129‐Adipoqtm1Chan/J) and wild‐type mice, and assessed parameters of hepatic metabolism, including mitochondrial function and fatty acid metabolism. We assessed the impact of adiponectin supplementation by administering adenovirus mediated full length adiponectin at the end of the second trimester of pregnancy, and comparing to control containing GFP.ResultsIn the third trimester, pregnant adiponectin−/− mice exhibited fasting hyperglycemia regardless of diet (9.2mmol/L vs. 7.7mmol/L in controls, p<0.05). These mice display impaired glucose and insulin tolerance relative to wild‐type controls. Pregnant adiponectin−/− mice develop hepatic steatosis, including a 3‐fold elevation in hepatic triglycerides (p<0.05). This was associated with altered hepatic lipid metabolism, including a 2.5 fold increase in fatty acid synthase expression (p<0.05), elevated circulating free fatty acids, triglycerides and cholesterol. Nearly 2‐fold reduction (p<0.05) in maximal mitochondrial respiration was observed via oxidative flux analyzer in hepatocytes of adiponectin −/− mice. Hepatocytes from pregnant adiponectin−/− mice show dramatically reduced respiratory capacity when using fatty acids alone, and display elevated synthesis and secretion of triglycerides and cholesterol. Gestational weight gain and food consumption were similar in knockout and wild‐type mice. Adiponectin supplementation to pregnant adiponectin−/− mice significantly improved glucose tolerance, prevented fasting hyperglycemia, and attenuated fatty liver development.ConclusionResults show that adiponectin deficiency is associated with altered hepatic lipid metabolism and hepatic steatosis during pregnancy. Consequently, adiponectin deficiency contributes to mid‐gestation insulin resistance and hyperglycemia characteristic of GDM. Moreover, adiponectin supplementation rescues the effects of adiponectin deficiency on insulin sensitivity and hepatic lipid metabolism.Support or Funding InformationResearch Manitoba, Children's Hospital Research Institute of Manitoba